Methods of Reducing Risk of Preterm Birth

ABSTRACT

This disclosure generally relates to methods for reducing the risk of preterm birth in a pregnant human female patient that include subcutaneous administration of HPC. The disclosure relates in part to the discovery that subcutaneous administration of HPC is actually feasible and can result in sufficient plasma levels of HPC in pregnant patients that can reduce the risk of preterm birth.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 15/709,941, filedSep. 20, 2017, which is a continuation of U.S. Ser. No. 15/143,867,filed on May 2, 2016, which claims priority to and the benefit of U.S.Ser. No. 62/155,076, filed Apr. 30, 2015 and U.S. Ser. No. filed62/250,189 filed Nov. 3, 2015, each of which is hereby incorporated byreference in its entirety.

BACKGROUND

Preterm delivery is a major health problem in the United States andworldwide. Preterm delivery is often defined as delivery before 37completed weeks of gestation and has been reported to be the majordeterminant of infant mortality in developed countries. Preterm deliveryis more common in the United States than in many other developedcountries, and is predominantly responsible for the relatively high rateof infant mortality in the United States as compared to many otherdeveloped countries. Over the past two decades, the rate of pretermdelivery in the United States has been reported to have increased from9% to 11%. In addition to preterm delivery, various otherpregnancy-related conditions are major health problems in the UnitedStates and worldwide. These include, for example, the delivery of lowbirth weight neonates, delivery of small for gestational age neonates,pregnancy-related complications, fetal mortality, neonatal morbidity,neonatal mortality, infant morbidity, infant mortality, and childhooddevelopmental delays.

Preterm delivery and other pregnancy-related conditions such as thedelivery of low birth weight neonates and/or small for gestational ageneonates have serious health, societal, and economic costs. For example,preterm delivery and the delivery of low birth weight neonates and/orsmall for gestational age neonates can lead to neonatal morbidity,longer stays in the neonatal intensive care unit, and a higher risk oflong term morbidities including, for example, cerebral palsy, mentalretardation, and learning disabilities.

A number of risk factors for preterm delivery and otherpregnancy-related conditions (e.g., previous pregnancy resulting inpreterm delivery, previous delivery of low birth weight and/or small forgestational age neonates) have been identified. For example, women whohave had a previous spontaneous preterm delivery are at high risk forpreterm delivery in subsequent pregnancies. Other risk factors forpreterm delivery include: tobacco use during pregnancy (e.g., smoking);infection; multiple gestations (twins, triplets, etc.); alcohol use,abuse, or dependence during pregnancy; substance use, abuse, ordependence during pregnancy; poor nutrition during pregnancy; stress,anxiety, and/or depression; insufficient weight gain during pregnancy;advanced maternal age; African-American descent; and low socio-economicstatus. Tobacco use or exposure, in particular smoking, during pregnancyis a significant risk factor for preterm delivery and other undesirablematernal, fetal, and neonatal outcomes.

Intramuscular injection of steroids such as 17-alpha-hydroxyprogesteronecaproate (“17-HPC” or “HPC”) in the gluteus maximus have been used toreduce the risk of preterm birth, but such injections can be painful,and/or may cause the buildup of scar tissue especially since theinjection must be repeated weekly for up to 21 weeks. Further,intramuscular injections involve the risk of nerve injury, especiallythe risk of sciatic nerve injury from dorsogluteal intramuscularinjections. There is a need for an alternative route of administrationthat may, for example, minimize pain and increase the likelihood ofpatient compliance.

SUMMARY

This disclosure generally relates to methods for reducing the risk ofpreterm birth in a pregnant human female patient that includesubcutaneous administration of HPC. The disclosure relates in part tothe discovery that subcutaneous administration of HPC is actuallyfeasible and can result in sufficient plasma levels of HPC in pregnantpatients that can reduce the risk of preterm birth.

For example, provided herein is a method of reducing the risk of pretermbirth in a pregnant human female patient, comprising subcutaneouslyadministering to said female human patient a dose of a pharmaceuticallyacceptable viscous non-aqueous liquid formulation comprisinghydroxyprogesterone caproate, wherein for example, the dose comprisesabout 187 mg to about 400 mg, about 200 to about 350 mg, or about 187 toabout 350 mg of hydroxyprogesterone caproate (e.g., the dose may beabout 250 mg of hydroxyprogesterone caproate, or about 260 mg to about350 mg, or about 275 mg to about 350 mg of hydroxyprogesteronecaproate), or e.g., about 275 mg or about 300 mg. Such disclosed methodsresult, in some embodiments, in a pharmacologically active plasmaconcentration of HPC in the patient.

Contemplated methods include subcutaneously administering discloseddoses and/or formulations into the upper anterior thigh or buttocks ofthe patient, into the upper arm of the patient, and/or into the abdomenof the patient. For example, a method of subcutaneously administeringdisclosed doses and/or formulation into the triceps area may providemore consistent results (e.g., plasma levels) (e.g., less variability)as compared to subcutaneously administering to other regions of thebody. For example, in some embodiments, subcutaneous administration tothe triceps area may produce higher blood levels than to administrationto the thigh.

Such contemplated methods may include administering a dose about weekly,or every other week, for example, subcutaneously administering aboutweekly, beginning about 16 weeks or later of gestation. For example,provided methods may include subcutaneous administration of a discloseddose effective such that the patient after administration has anAUC_(0-t) of about 90%, 80%, or 79% or less, about 75% or less, or about74% of an AUC_(0-t) as compared to the AUC_(0-t) of a patientadministered the same dosage amount of hydroxyprogesterone caproateintramuscularly, and/or upon subcutaneous administration, the patientmay have a C_(max) of about 120%, 110%, about 105%, about 100%, or about90%, 80%, 79% or less, about 70% or less, or about 69% of the C_(max) ascompared to the C_(max) of patient administered the same dosage amountof hydroxyprogesterone caproate intramuscularly. In other embodiments,subcutaneous administration in upper arm may result in 10-20% morevolume as compared to intramuscular administration.

For example, provided herein in some embodiments, are methods whereinabout 24 hours after subcutaneous administration of a 275 mg or a 250 mgdose of hydroxyprogesterone caproate, the human female pregnant patienthas a mean plasma concentration of about 3 to about 5 ng/mL, or e.g.,about 5 to about 12 ng/mL (e.g., a mean of about 8 ng/mL) e.g., about 24hours or at about 48 hours or after subcutaneous administration of a 250mg dose of hydroxyprogesterone caproate, the patient has a mean plasmaconcentration of about 4 ng/mL hydroxyprogesterone caproate.

For example, provided herein, in some embodiments, are disclosed methodsof subcutaneous administration of about four consecutive doses, fiveconsecutive doses, six consecutive doses, or more than six consecutivedoses (e.g., doses of compositions as disclosed herein), a human femalepregnant patient achieves a mean plasma concentration of about 9 ng/mLor more of the hydroxyprogesterone caproate.

Disclosed methods include subcutaneously administering a dose of adisclosed pharmaceutically acceptable viscous non-aqueous liquidformulation, which may have a volume of about 0.70 mL to about 2 mL,about 1.0 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, or about 1.4 mL,e.g., a dose of the pharmaceutically acceptable viscous non-aqueousliquid formulation may have a volume of about 1.1 mL to about 1.4 mL,about 1.1 mL to about 1.2 mL or about 1.3 mL to about 1.4 mL, about 1.1to about 1.3 mL, or about 1.1 mL to about 1.6 mL, or about 1.4 mL.Contemplated doses include doses having a concentration of about 250mg/mL of the hydroxyprogesterone caproate, or about 260 mg/mL to about330 mg/mL.

In another embodiment, a method of reducing the risk of preterm birth ina pregnant human female patient is provided, comprising: subcutaneouslyadministering (e.g., into the upper anterior thigh or buttock, upper arm(e.g. triceps area) and/or abdomen) to said female human patient a doseof about 1.0 to about 1.6 mL (e.g., about 1.2 to about 1.4 mL, or about1.3 to about 1.4 mL) of a pharmaceutically acceptable viscousnon-aqueous liquid formulation having a hydroxyprogesterone caproateconcentration of about 250 mg/mL. In another embodiment, contemplatedmethods comprise administering about 1.0 mL of a disclosedpharmaceutically acceptable viscous non-aqueous liquid formulationhaving a hydroxyprogesterone caproate concentration of about 260 mg/mLto about 330 mg/mL (e.g., about 270 to about 290 mg/mL or about 260mg/mL to about 300 mg/mL).

Contemplated methods as disclosed herein may include subcutaneousadministration to a female human patient of a pharmaceuticallyacceptable viscous non-aqueous liquid formulation that includes HPC(e.g., 17-α hydroxyprogesterone caproate) and also comprises apharmaceutically acceptable oil having a viscosity of about 250-1000 cPat 25° C. In some embodiments, a contemplated formulation for use in thedisclosed methods is a pharmaceutically acceptable viscous non-aqueousliquid formulation that consists essentially of hydroxyprogesteronecaproate, castor oil and benzyl benzoate. In another embodiment, acontemplated dose may have a concentration of 250 mg/mL ofhydroxyprogesterone caproate. In a different embodiment, a contemplateddose may have a concentration of about 260 mg/mL to about 310 mg/mL(e.g., about 270 to about 290 mg/mL).

In some embodiments, disclosed methods include subcutaneouslyadministering a dose to a pregnant human female patient beginningbetween about 16 weeks of gestation, zero days, to about 21 weeks, sixdays of gestation, and continued until about 37 weeks of gestation ordelivery, whichever occurs first. In some embodiments, a pregnant humanfemale patient has a singleton pregnancy. For example, a pregnant humanfemale patient who has a history of singleton spontaneous preterm birth.

In another embodiment, disclosed methods may include subcutaneouslyadministering a first dose of about 260 mg to about 300 mg ofhydroxyprogesterone caproate once or twice for a first week, andsubcutaneously administering a second dose weekly of about 250 mg toabout 260 mg of hydroxyprogesterone caproate. For example, a dose may beadministered as a first dose (that e.g., comprises about 250 to about300 mg of hydroxyprogesterone caproate) twice a week for the first 1 to2 weeks, and administered weekly thereafter.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A and FIG. 1B depict the plasma concentration ofhydroxyprogesterone caproate after administration. FIG. 1A depicts acomparison of plasma concentration of hydroxyprogesterone caproate(ng/mL) over 144 hours after administration by IM or SQ injections of250 mg hydroxyprogesterone caproate contained in 1 mL. FIG. 1B depicts acomparison of plasma concentration of hydroxyprogesterone caproate(ng/mL) over 168 hours after administration by IM (1 mL, 250 mg HPC) orSQ injections into upper arm (triceps area) (1.3 mL, 325 mghydroxyprogesterone caproate.

FIG. 2 shows the geometric mean plasma concentrations of HPC after SCand IM—linear (left panel) and semi-logarithmic (right panel).

FIG. 3 shows the solubility of 17-HPC in different benzyl benzoateratios.

DETAILED DESCRIPTION

Described herein are methods for reducing the occurrence of pretermdelivery and/or reducing the occurrence of other pregnancy-relatedconditions such as delivery of low birth weight neonates, delivery ofsmall for gestational age neonates, pregnancy-related complications,fetal mortality, neonatal morbidity, neonatal mortality, infantmorbidity, infant mortality, and childhood developmental delays in ahuman female patient (e.g., a human female patient pregnant with asingleton or with multiple fetuses). For example, methods disclosedherein are effective for reducing the occurrence of preterm delivery ina pregnant human female subject at risk for preterm delivery. Riskfactors for preterm delivery and/or other pregnancy-related conditionsinclude previous preterm delivery, exposure to tobacco smoke, exposureto tobacco smoke residue, use of smokeless tobacco, substance use orabuse or dependence, alcohol use or abuse or dependence, stress,anxiety, depression, poor nutritional status, insufficient weight gainduring pregnancy, advanced maternal age, low socio-economic status, andcombinations thereof. Advantageously, the methods disclosed hereininclude subcutaneous (SQ) administration of 17-HPC and can provideeffective treatment to pregnant human females at risk of e.g. a pretermdelivery. SQ injections can be less painful, and/or can involve lessrisk of complications than IM injections.

A. Preterm Delivery

As noted, preterm delivery is a major health problem in the U.S. andworldwide. Preterm delivery is often defined to include any deliverybefore 37 weeks or before 35 weeks of gestation. The gestational age ofan embryo or fetus may be calculated using ultrasound and/or from thedate of the woman's last menstrual period or from 14 days beforeconception if the date of conception is known. For purposes ofdetermining the effectiveness of the methods of the present invention,preterm delivery can be defined as any live birth occurring prior to 37weeks of gestation, prior to 36 weeks of gestation, or prior to 35 weeksof gestation. Since viability may occur for live births prior to 35weeks of gestation, preterm delivery may also be defined as any livebirth occurring between 20 and 36 weeks of gestation.

B. Low Birth Weight/Small for Gestational Age Neonates

Contemplated herein in part are methods of reducing the risk ofdelivering a low birth weight infant in a pregnant human female patient,comprising subcutaneously administering to the patient a dose ofhydroxyprogesterone caproate as disclosed herein. Neonates having arelatively low birth weight and/or relatively small size are generallyassociated with a higher risk of various complications as compared toneonates having a weight and/or size within normal ranges, including anincreased risk for neonatal morbidity and mortality, and infantmorbidity and mortality. As used herein, the term “low birth weightneonates” encompasses low birth weight neonates (neonates having aweight at birth of less than about 2500 g (about 5.5 pounds)), very lowbirth weight neonates (neonates having a weight at birth of less thanabout 1500 g (about 3.3 pounds)), and extremely low birth weightneonates (neonates having a weight at birth of less than about 1000 g(about 2.2 pounds)). A neonate is suitably classified as a small forgestational age neonate if his or her weight at birth is below the 10thpercentile for gestational age, as measured according to the acceptedstandards published by Battaglia et al., or if birth weight and/orlength are at least 2 standard deviations (SDs) below the mean forgestational age, as described by Lee et al. See Battaglia et al., APractical Classification of Newborn Infants by Weight and GestationalAge, J. Pediatrics 71(2):159-63 (August 1967) and Lee et al.,International Small for Gestational Age Advisory Board ConsensusDevelopment Conference Statement: Management of Short Children BornSmall for Gestational Age, Apr. 24-Oct. 1, 2001, Pediatrics 111(6 Pt.1):1253-61 (June 2003), both of which are incorporated by referenceherein for all relevant purposes.

C. Pregnancy-Related Complications

Contemplated herein in an embodiment are methods of reducing the riskpregnancy related complications in a pregnant human female patient,comprising subcutaneously administering to the patient a dose ofhydroxyprogesterone caproate as disclosed herein. Pregnancy-relatedcomplications contemplated include, for example, placental abruption,placenta previa, and hypertension-related disorders (e.g., preeclampsiaand eclampsia). These complications are generally known to contribute topreterm delivery, delivery of low birth weight neonates, etc. Thus,reducing the occurrence of these complications likewise reduces theoccurrence of preterm delivery, delivery of low birth weight neonates,etc.

D. Mortality

Contemplated herein are methods of reducing the risk of neonatalmortality in a pregnant human female patient, comprising subcutaneouslyadministering to the patient a dose of hydroxyprogesterone caproate asdisclosed herein. Fetal mortality includes any death of a fetus at 20weeks of gestation or later or any death of a fetus weighing more than500 g. Fetal mortality includes both antepartum deaths (i.e., deathsoccurring before birth) and intrapartum deaths (i.e., deaths occurringduring labor and delivery).

Neonatal mortality refers to the death of a live-born neonate within thefirst 28 days of life. Neonatal mortality includes both early neonatalmortality (i.e., death of a live-born neonate within the first sevendays of life) and late neonatal mortality (i.e., death of a live-bornneonate after the first seven days of life but within the first 28 daysof life). Together, fetal mortality and early neonatal mortality areoften referred to as “perinatal mortality.” Thus, “perinatal mortality”refers to deaths occurring between 20 weeks of gestation and the end ofthe 7th day after delivery. Infant mortality includes deaths which occurafter 28 days of life, but before one year.

E. Morbidity and Developmental Delays

Also contemplated herein are methods of reducing the risk of neonatalmorbidity and/or development delays in a neonate that includesubcutaneously administering to a pregnant human female patient a doseof hydroxyprogesterone caproate as disclosed herein. Neonatal morbidityand infant morbidity refer to any disease, disorder, symptom, or otherundesirable outcome occurring in a neonate or an infant, respectively.Developmental delays occur when children have not yet reached expecteddevelopmental milestones by the expected time period. Neonatalmorbidity, infant morbidity, and childhood developmental delaysencompass a number of conditions affecting neonates, infants, and/orchildren, including, but not limited to, transient tachypnea,respiratory distress syndrome, bronchopulmonary dysplasia, a need forventilatory support/mechanical ventilation, a need for supplementaloxygen, intraventricular hemorrhage, necrotizing enterocolitis, patentductus arteriosus, retinopathy, sepsis, sudden infant death syndrome(SIDS), cerebral palsy, mental retardation, learning disabilities, andbehavioral disorders. Various additional diagnoses associated withneonatal morbidity, infant morbidity, and/or childhood developmentaldelays include anemia, arthritis, asthma, diabetes, diarrhea, colitis,ear infections, eczema, food or digestive allergies, hay fever,respiratory allergies, seizures, severe headaches or migraines, sicklecell disease, and stuttering and stammering. Other conditions includecommunication problems, problems with problem solving, attention orlearning problems (e.g., attention-deficit hyperactivity disorder(ADHD)), autism, problems carrying out activities and problems withcoordination.

II. Risk Factors

An embodiment provided herein is a method of reducing the risk ofpreterm birth in a pregnant human female patient (e.g., a human femalepatient that has one or more risk factors (e.g., one or more previouspreterm births and/or another risk factor as outlined below)),comprising subcutaneously administering to the patient a dose ofhydroxyprogesterone caproate as disclosed herein. A variety of riskfactors that may be associated with the above-listed pregnancy-relatedconditions alone or in combination are detailed below. An exemplary riskfactor is a patient that has a history of singleton spontaneous pretermbirth. Various risk factors listed below are in connection with exposureto tobacco (e.g., tobacco smoke or tobacco smoke residue). Other riskfactors that may contribute to and/or cause one or morepregnancy-related conditions include substance use or abuse ordependence, alcohol use or abuse or dependence, stress, poor nutritionalstatus, insufficient weight gain during pregnancy, advanced maternalage, low socio-economic status, and combinations thereof. Behaviorsunfavorable to a subject's health such as smoking tend to cluster (e.g.,women who smoke are also more likely to have poor diets). Thus, manywomen exhibit more than one risk factor for the pregnancy-relatedconditions, which may increase the risk of occurrence of thepregnancy-related conditions. For example, the occurrence of more thanone of the following risk factors are commonly exhibited by a singlesubject: exposure to tobacco smoke, stress, poor nutritional status, lowsocio-economic status, alcohol use, abuse, or dependence. Thus, invarious preferred embodiments the methods of the present invention aredirected to reducing the occurrence of one or more pregnancy-relatedconditions in a pregnant human female subject exhibiting at least onerisk factor selected from the group consisting of exposure to tobaccosmoke, stress, poor nutritional status, low socio-economic status,alcohol use or abuse or dependence, and combinations thereof.

A. Tobacco

One significant risk factor for preterm delivery and the otherpregnancy-related conditions is exposure of the pregnant human female totobacco smoke during pregnancy. This exposure may occur in many forms.Exposure to tobacco smoke includes smoking of tobacco products by thepregnant human female subject herself, as well as passive smoking viathe inhalation of smoke from tobacco products used by others (commonlyreferred to as second-hand smoke or environmental tobacco smoke). Ineither case, the tobacco smoke may be smoke generated by the use of, forexample, a cigarette, a cigar, or a pipe, or any other implement whichgenerates smoke from tobacco. A primary means of exposure of subjects totobacco smoke in accordance with the present invention is smoking by thepregnant human female subject.

Tobacco smoke residue typically contains nicotine, heavy metals,carcinogens, carbon monoxide, reactive oxygen species, and othertoxicants which can contribute to or cause one or more pregnancy-relatedcomplications. Exposure to tobacco smoke residue or the use of smokelesstobacco may pose similar risks to the pregnant human female subject asexposure to tobacco smoke. Exposure to tobacco smoke residue includesexposure to toxicants which accumulate on environmental surfaces inareas wherein tobacco products have been smoked. Tobacco smoke residueis commonly referred to as “third-hand smoke.” Tobacco smoke residue canaccumulate on virtually any environmental surface, including, but notlimited to, hair, clothing, furniture, carpeting, and automobileupholstery.

Use of smokeless tobacco is also a risk factor for the above-notedpregnancy-related conditions and includes use of any type of tobaccothat is consumed other than by smoking. For instance, smokeless tobaccoincludes, but is not limited to, dipping tobacco, chewing tobacco,snuff, creamy snuff, snus, tobacco gum, dissolvable tobacco, topicaltobacco paste, and tobacco water.

B. Substance Use, Abuse, and/or Dependence

Substance use, abuse, or dependence includes the use or abuse of, or thedependence on, drugs commonly referred to as “street drugs” (e.g.,marijuana and cocaine) and/or the use or abuse of, or the dependence on,prescription drugs other than as directed by a physician. Substance userefers to use which is sufficient to result in a positive result on anytest commonly used for screening for substance use including, forexample, blood tests, urine tests, etc. Substance abuse and substancedependence are suitably diagnosed according to the diagnostic criteriawell known to those skilled in the art, such as those set forth in theDiagnostic and Statistical Manual of Mental Disorders (AmericanPsychiatric Association, 4th ed., text revision) (DSM-IV-TR), which isincorporated by reference herein for all relevant purposes. Substanceuse, abuse, or dependence may suitably refer to the use or abuse of, orthe dependence on, for example, opioids, depressants, hallucinogens,stimulants, hypnotics, analgesics, inhalants, sedatives, anxiolytics, orcombinations thereof. For instance, substance use, abuse, or dependencemay include, but is not limited to, the use or abuse of, or thedependence on, marijuana, cocaine, heroin, methamphetamine, anabolicsteroids, 3,4-methylenedioxymethamphetamine (MDMA (ecstasy)),psilocybin, psilocin, lysergic acid diethylamide (LSD), morphine,oxycodone, phencyclidine (also referred to as phenylcyclohexylpiperidineor PCP).

C. Alcohol Use, Abuse, and/or Dependence

Alcohol use, abuse, or dependence generally includes the use or abuseof, or the dependence on, any alcohol-containing product, such as beer,wine, or liquor. Alcohol use may specifically refer to confirmed use ofalcohol during pregnancy. High risk alcohol use during pregnancy isdefined as confirmed use of alcohol sufficient to produce high bloodalcohol levels (100 mg/dL or greater) delivered at least weekly in earlypregnancy. Alcohol abuse and alcohol dependency are suitably diagnosedaccording to the diagnostic criteria well known to those skilled in theart, such as those set forth in the Diagnostic and Statistical Manual ofMental Disorders, which is incorporated by reference herein for allrelevant purposes.

D. Stress/Anxiety/Depression

Experiencing relatively high stress levels may put pregnant women at anincreased risk for one or more of the above-noted pregnancy-relatedconditions. Stress levels are suitably measured by a method well knownto one skilled in the art, for example, by psychometric scales includingthe stress component of the Abbreviated Scale for the Assessment ofPsychosocial Status in Pregnancy tool, the Stressful Life Events scale(part of the CDC's Pregnancy Risk Assessment and Monitoring System(PRAMS)) and the Modified Life Experiences Survey. A stress levelexceeding the pre-defined values for one of these scales would generallybe considered to increase the risk for the pregnancy-related conditionsdiscussed above. Stress may be caused, for example, by life events suchas divorce, illness, injury, job loss, or the like.

In addition, women who have been diagnosed with anxiety and/ordepression according to the standards generally used by medicalprofessionals (e.g., those set forth in the Diagnostic and StatisticalManual of Mental Disorders, which is incorporated by reference hereinfor all relevant purposes) may also be at increased risk for thepregnancy-related conditions discussed above.

E. Nutritional Status

Poor nutritional status may put a pregnant human female at an increasedfor the one or more of the above-noted pregnancy-related conditions.Nutritional status may be assessed by weight gain during pregnancy basedon pre-pregnancy body mass index (BMI) according to the Institute ofMedicine recommendations. See Institute of Medicine, Weight Gain DuringPregnancy: Reexamining the Guidelines (2009), which is incorporated byreference herein for all relevant purposes. For example, a pregnanthuman female subject will generally be considered to have a poornutritional status if weight gain during pregnancy is insufficientaccording to these guidelines.

F. Weight Gain

A pregnant human female subject is considered to have gainedinsufficient weight during pregnancy if the subject had a pre-pregnancyBMI of less than about 18.5 kg/m² and total weight gain was less thanabout 12.7 kg (i.e., less than about 28 lbs), had a pre-pregnancy BMI offrom about 18.5 to about 24.9 kg/m′ and total weight gain was less thanabout 11.3 kg (i.e. less than about 25 lbs), had a pre-pregnancy BMI ofabout 25.0 to about 29.9 kg/m² and total weight gain was less than about6.8 kg (i.e., less than about 15 lbs), or had a pre-pregnancy BMI of atleast about 30.0 kg/m′ and total weight gain was less than about 5.0 kg(i.e., less than about 11 lbs). Additionally or alternatively, apregnant human female subject in the second or third trimester isconsidered to have gained insufficient weight during pregnancy if thesubject had a pre-pregnancy BMI of less than about 18.5 kg/m′ and totalweight gain during the second and third trimesters was less than about0.45 kg/week (i.e., less than about 1 lb/week), had a pre-pregnancy BMIof from about 18.5 to about 24.9 kg/m² and total weight gain during thesecond and third trimesters was less than about 0.36 kg/week (i.e., lessthan about 0.8 lbs/week), had a pre-pregnancy BMI of from about 25.0 toabout 29.9 kg/m² and total weight gain during the second and thirdtrimesters was less than about 0.23 kg/week (i.e., less than about 0.5lbs/week), or had a pre-pregnancy BMI of at least about 30.0 kg/m² andtotal weight gain during the second and third trimesters was less thanabout 0.18 kg/week (i.e., less than about 0.4 lbs/week).

G. Maternal Age

Generally, as maternal age increases so too does the risk of occurrenceof preterm delivery and/or one or more other pregnancy-relatedconditions. By advanced maternal age, it is meant that the pregnanthuman female subject is at least 35 years of age at the time ofdelivery.

H. Socio-Economic Status

A pregnant human female subject is suitably considered to have a lowsocio-economic status if the pregnant human female subject's familyand/or household income is at or below the federal poverty level or ifthe pregnant human female subject is eligible for the Medicaid program

III. Steroid Hormones

The methods disclosed herein for reducing the occurrence of pretermdelivery and/or one or more other pregnancy-related conditions comprisesubcutaneous administration of a pharmaceutical composition comprising asteroid hormone. For example, a contemplated progestin for use in themethods disclosed herein is 17-alpha-hydroxyprogesterone or apharmacologically active derivative or analog thereof. Suitablederivatives of 17-alpha-hydroxyprogesterone include esters of17-alpha-hydroxyprogesterone, and in particular17-alpha-hydroxyprogesterone caproate (17-HPC), which has been approvedfor human use by the United States Food and Drug Administration (FDA).Other esters of 17-alpha-hydroxyprogesterone may also suitably be used.In accordance with various embodiments, contemplated methods includesubcutaneous administration of a pharmaceutical composition thatcomprises 17-HPC.

IV. Administration

Contemplated treatments of a pregnant human female subject with asteroid hormone typically begins during the first or second trimester ofpregnancy (i.e., during weeks 1-27 of gestation) and continues untilrelatively late in the third trimester or until delivery, whicheveroccurs first. However, it is anticipated that the benefits of thedisclosed methods will still be realized even if steroid hormonetreatment is not initiated until the third trimester. Thus, for example,treatment with a steroid hormone is typically initiated at between 1week and about 35 weeks of gestation and continues until about 37 weeksof gestation, or delivery, whichever occurs first. Alternatively, thesteroid hormone treatment is suitably initiated at between about 12weeks and about 30 weeks of gestation and continues until about 36 weeksof gestation, or delivery, whichever occurs first. In some methods oftreatment, the steroid hormone treatment is initiated at between about16 weeks, zero days, to about 21 weeks (or 20 weeks, six days ofgestation, or in another embodiment, initiated at about 25 weeks) andcontinues until about 36 weeks or 37 weeks of gestation, or untildelivery of an infant, whichever occurs first. In an embodiment,disclosed methods of treatment, including treatment with a steroidhormone, is initiated during the second or third trimester. Thus, inaccordance with various disclosed methods of treatment, subcutaneoustreatment with a steroid hormone (e.g., 17-HPC) is initiated at 13 weeksof gestation or later (e.g., at or around 28 weeks of gestation orlater).

Disclosed methods include subcutaneous administration of a steroidhormone, e.g., 17-alpha-hydroxyprogesterone caproate (17-HPC). Forexample, contemplated methods may include administration of a viscousnon-aqueous liquid formulation comprising 17-HPC; for example a viscousnon-aqueous liquid formulation comprising 17-HPC and a pharmaceuticallyacceptable oil (e.g., castor oil). In an embodiment, a method oftreating a pregnant human female patient in need of reducing the risk ofpreterm birth is provided comprising subcutaneously administering aformulation comprising 17-HPC and a mixture of non-aqueous solvents suchas benzyl benzoate and castor oil. Contemplated formulations mayoptionally additionally include benzyl alcohol.

Contemplated methods as disclosed herein may include subcutaneousadministration of a disclosed composition into e.g., the upper anteriorthigh, buttocks, upper arm (e.g., triceps area), or abdomen of thepatient.

In various methods of treatment, a disclosed pharmaceutical compositionis administered at an interval of once a week or exceeding once perweek, for example, administered about weekly beginning about 16 weeks ofgestation (e.g., beginning between about 16 weeks, zero days and about20 weeks, six days of gestation), until about 37 weeks of gestation oruntil delivery. For example, the pharmaceutical composition may beadministered once every other week, once monthly, once every two months,or once every three months. In various other embodiments, thepharmaceutical composition is administered about once weekly, or at aninterval of less than one week (e.g., daily or every other day).

In one embodiment, contemplated methods include subcutaneouslyadministering a pharmaceutical composition comprising 17-HPC to apregnant human female subject on a weekly basis, or more than once aweek basis, e.g. subcutaneously administering 17-HPC every 7 days, every8 days, every 9 days, every 10 days, every 11 days, every 12 days, every13 days, or every other week. For example, contemplated methods includeadministering a disclosed pharmaceutical composition that includes17-HPC and an oil, e.g. castor oil, on an about weekly, or amore-than-once-a-week basis.

Disclosed methods include subcutaneous administration of 17-HPC, whereinupon subcutaneous administration of one, two, three or more doses (e.g.,on a weekly basis) the patient has an AUC_(0-t) of about 90%, 80%, 79%or less, about 75% or less, or about 74% (e.g. about 79% to about 74%)as compared to the AUC_(0-t) of a patient administered the same dosageamount of hydroxyprogesterone caproate intramuscularly. Contemplatedmethods include subcutaneous administration of 17-HPC, wherein uponsubcutaneous administration of one, two, three or more doses (e.g., on aweekly basis) the patient has a C_(max) of about 120%, about 110%, about100%, or, about 90%. 80%, 79% or less, about 70% or less or about 69%(e.g., 79% to 69% or less of the C_(max)) as compared to the C_(max) ofpatient administered the same dosage amount of hydroxyprogesteronecaproate intramuscularly.

Subcutaneous administration contemplated herein provides for efficaciousplasma levels of 17-HPC in patients. For example, 24 hours aftersubcutaneous administration of a 250 mg dose of hydroxyprogesteronecaproate to a patient as contemplated by methods disclosed herein, thepatient has a mean plasma concentration of about 3 to about 5 ng/mL, orabout 5-12 ng/mL (e.g., about 7-8 ng/mL) e.g., 24 hours or 48 hoursafter subcutaneous administration of a 250 mg dose ofhydroxyprogesterone caproate. For example, after administration of a 250mg dose the patient may have has a mean plasma concentration of about 8ng/mL hydroxyprogesterone caproate.

Subcutaneous administration contemplated herein may provide forefficacious plasma levels of 17-HPC in patients after one or moreconsecutive doses, for example, after subcutaneous administration ofabout four consecutive doses, five consecutive doses, six consecutivedoses or more than six consecutive doses as disclosed by methodsdescribed herein, the patient achieves a mean plasma concentration ofabout 8 or 9 ng/mL or more of the hydroxyprogesterone caproate.

Pharmaceutical compositions contemplated by methods disclosed herein mayinclude about 100 milligrams (mg) to about 3000 mg of 17-HPC. Forexample, contemplated methods include administering a pharmaceuticalcomposition that includes 17-HPC and an oil, e.g. castor oil, on aonce-monthly basis. Such pharmaceutical compositions may include atleast about 100 mg of 17-HPC, at least about 200 mg of 17-HPC, at leastabout 300 mg of 17-HPC, at least about 400 mg of 17-HPC, at least about500 mg of 17-HPC, at least about 750 mg of 17-HPC, at least about 1000mg of 17-HPC, at least about 1500 mg of 17-HPC, at least about 2000 mgof 17-HPC, or at least about 2500 mg of 17-HPC. In accordance with thisand various other embodiments, such pharmaceutical compositions mayfurther include less than about 3000 mg of 17-HPC, less than about 2500mg of 17-HPC, less than about 2000 mg of 17-HPC, less than about 1500 mgof 17-HPC, less than about 1000 mg of 17-HPC, less than about 500 mg of17-HPC, or less than about 250 mg of 17-HPC.

For example, contemplated compositions for subcutaneous administrationas disclosed herein may include compositions having 17-HPC solubilizedwith a mixture that includes benzyl benzoate and an oil such as castoroil, e.g., solubilized with a mixture having about 53 to about 88 weightpercent benzyl benzoate, about 69 to about 88 weight percent benzylbenzoate, or about 63 to about 76 weight percent benzyl benzoate withthe remainder castor oil (and optionally benzyl alcohol). Contemplatedcompositions may include about 21 to about 34 (e.g., about 22 to about30) weight percent 17-HPC, and an oil such as castor oil, and optionallyabout 1 to 2 weight percent benzyl alcohol. A contemplated unit dose forexample, may have about 1.1 to about 1.3 mg/mL or about 1.0 to about 1.2mg/mL of 17-HPC.

In another embodiment, contemplated methods include subcutaneouslyadministering a pharmaceutical composition comprising 17-HPC to apregnant human female subject on a once-weekly basis. For example,contemplated methods include administering a pharmaceutical compositionthat includes 17-HPC and an oil, e.g. castor oil, on a once-weeklybasis. Such pharmaceutical compositions may include at least about 50 mgof 17-HPC, at least about 75 mg of 17-HPC, at least about 100 mg of17-HPC, at least about 150 mg of 17-HPC, at least about 200 mg of17-HPC, at least about 250 mg of 17-HPC (e.g., about 260 mg to about 390mg, e.g. about 260 to about 340 mg, or e.g., 280 mg to about 360 mg or290 mg to about 380 mg), at least about 500 mg of 17-HPC, at least about750 mg of 17-HPC, or at least about 1000 mg of 17-HPC. In accordancewith this and various other embodiments, such pharmaceuticalcompositions may further include less than about 1600 mg of 17-HPC, lessthan about 1500 mg of 17-HPC, less than about 1250 mg of 17-HPC, lessthan about 1000 mg of 17-HPC, less than about 800 mg of 17-HPC, lessthan about 500 mg of 17-HPC, or less than about 350 mg 17-HPC. Forexample, a contemplated method includes subcutaneously administering apharmaceutical composition comprising 17-HPC to a pregnant human femalesubject on a once-weekly basis, said pharmaceutical composition suitablyincluding from about 50 mg to about 1600 mg of 17-HPC, from about 100 mgto about 800 mg of 17-HPC, or about 260 to about 350 mg, or about 250 mg17-HPC.

For example, contemplated methods may include subcutaneouslyadministering a dose of a disclosed pharmaceutically acceptable viscousnon-aqueous liquid formulation having about 187 mg to about 400 mg17-HPC, where the dose has a volume of about 0.70 mL to about 2 mL,about 1.0 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, or about 1.4 mL,e.g., a volume of about 1.1 mL to about 1.4 mL, about 1.3 mL to about1.4 mL, about 1.1 mL to about 1.6 mL, about 1.1 to about 1.3 mL, about1.1 to about 1.2 mL, or about 1.4 mL.

Contemplated herein are methods that include subcutaneous administrationof about 1.1 mL to about 1.4 mL (or e.g. 1.0 to 1.2 mL, e.g., 1.1 to 1.2mL) of a pharmaceutically acceptable viscous non-aqueous liquidformulation having a concentration of about 250 mg/mL ofhydroxyprogesterone caproate, or about 260 mg/mL to about 290 mg/mL of17-HPC.

In still another embodiment, contemplated methods include subcutaneouslyadministering to a pregnant human female subject a first pharmaceuticalcomposition comprising 17-HPC on a once- or twice-weekly basis for 1 to2 weeks, followed by a second pharmaceutical composition comprising17-HPC on a once-weekly basis for the remainder of the treatment. Inthis embodiment, it is contemplated that both the first and secondpharmaceutical compositions will include 17-HPC and an oil, e.g. castoroil, and that the first pharmaceutical composition will include an equalor greater amount of 17-HPC than the second pharmaceutical composition.Said first pharmaceutical compositions may include at least about 25 mgof 17-HPC, at least about 50 mg of 17-HPC, at least about 100 mg of17-HPC, at least about 250 mg of 17-HPC, at least about 500 mg of17-HPC, at least about 750 mg of 17-HPC, at least about 1000 mg of17-HPC, at least about 1500 mg of 17-HPC. Said second pharmaceuticalcompositions may include at least about 25 mg of 17-HPC, at least about50 mg of 17-HPC, at least about 100 mg of 17-HPC, at least about 250 mgof 17-HPC, at least about 500 mg of 17-HPC, at least about 750 mg of17-HPC, at least about 1000 mg of 17-HPC, at least about 1500 mg of17-HPC, for example, wherein the first pharmaceutical compositioncontains an equal or greater amount of 17-HPC than the secondpharmaceutical composition. In accordance with this and various otherembodiments, said first pharmaceutical composition may include less thanabout 1600 mg 17-HPC, less than about less than about 1250 mg of 17-HPC,less than about 1000 mg of 17-HPC, less than about 800 mg of 17-HPC,less than about 500 mg of 17-HPC, or less than about 350 mg 17-HPC.Similarly, said second pharmaceutical composition may include less thanabout 1600 mg 17-HPC, less than about 1250 mg of 17-HPC, less than about1000 mg of 17-HPC, less than about 800 mg of 17-HPC, less than about 500mg of 17-HPC, or less than about 350 mg 17-HPC, wherein the firstpharmaceutical composition contains an equal or greater amount of 17-HPCthan the second pharmaceutical composition. For example, a contemplatedmethod includes subcutaneously administering to a pregnant human femalesubject, a first pharmaceutical composition comprising 17-HPC, once- ortwice-weekly for one to two weeks, followed by a second pharmaceuticalcomposition comprising 17-HPC once-weekly for the remainder of thetreatment. The first pharmaceutical composition may include from about50 mg to about 1600 mg of 17-HPC, from about 100 mg to about 800 mg of17-HPC, or about 250 mg 17-HPC. The second pharmaceutical compositionmay include from about 50 mg to about 1600 mg of 17-HPC, from about 100mg to about 800 mg of 17-HPC, or about 250 mg 17-HPC wherein the firstpharmaceutical composition contains an equal or greater amount of 17-HPCthan the second pharmaceutical composition.

Generally, along with the contemplated steroid hormone(s), e.g., 17-HPC,disclosed methods include a pharmaceutical composition that additionallycontains one or more pharmaceutically acceptable excipients. Forexample, provided herein is a pharmaceutically acceptable viscousnon-aqueous liquid formulation that includes 17-HPC. For example, thepharmaceutical composition may contain one or more diluents, one or morecarriers, one or more solvents, one or more viscosity enhancementagents, one or more buffers, one or more preservatives, one or moredyes, one or more absorption enhancers, and/or one or more biodegradablepolymers. For example, contemplated methods include subcutaneouslyadministering a pharmaceutical composition to a pregnant female subject,said pharmaceutical composition comprising 17-HPC and a viscous oil e.g.with a 250-1000 cP at 25° C. In an embodiment, methods disclosed hereininclude subcutaneous administration of an essentially preservative freepharmaceutical composition that includes 17-HPC and castor oil. Forexample, methods disclosed herein include subcutaneous administration ofa pharmaceutical composition that consists essentially of 17-HPC, castoroil, and benzyl benzoate.

V. Pain Measurement

In an embodiment, disclosed methods that include subcutaneousadministration may provide significant pain reduction for the patientbeing treating, as compared for example to IM administration of 17-HPC.Subcutaneous administration allows for use of shorter needles (e.g., ½″vs 1.5″) and narrower gauge needles (27 G vs 21 G). Pain may be measuredin any of several ways that will be readily apparently to one of skillin the art. For example, pain may be measured using a Visual AnalogScale (VAS), wherein patients are presented with a horizontal line 100mm long, representing the pain scale from no pain at one end, to worstpossible pain on the other. Patients mark the scale with a vertical lineintersecting the horizontal line at the point they believe indicatestheir level of pain. The distance from 0 to the patient's indicated lineis measured in millimeters, which gives a numerical indication of thepatient's indicated pain level from 0 to 100.

Alternatively, pain can be using a Numerical Rating Scale (NRS-11) an11-point scale for patient self-reporting of pain. In the NRS-11, a painrating of 0 indicates no pain, 1-3 indicate mild pain (pain which isnagging, annoying, but interferes little with activities of daily living(ADLs), 4-6 indicate moderate pain (pain which interferes significantlywith ADLs), and 7-10 indicate sever pain (pain which is disabling, andrenders the patient unable to perform ADLs).

EXAMPLES

The examples which follow are intended in no way to limit the scope ofthis invention but are provided to illustrate aspects of the disclosedmethods. Many other embodiments of this invention will be apparent toone skilled in the art.

Example 1

An open-label, randomized, single-dose, two-period, two-treatment,four-sequence, crossover study was conducted to compare equal 250 mgdoses of 17-HPC injections, 250 mg/ml given as either a 1 mL deep IMinjection to the upper outer quadrant of the gluteus maximus or a 1 mLSQ injection to the upper anterior thigh. The study was conducted with12 healthy, non-tobacco using postmenopausal adult women. The subjectswere given the SQ injection in one study period and the IM injection inthe other study period according to the four-sequence randomizationschedule. Blood was taken at 4, 24, 48, 72, 96, 120 and 144-hourspost-treatment, and plasma concentrations of 17-HPC were measured. Theinterval between doses was 21 days. The analytical data were used toestimate the pharmacokinetic parameters AUC_(0-t), C_(max), and T_(max).

SQ injections of 17-HPC resulted in an average AUC_(0-t) value of 458.5ng·hr/mL, and average C_(max) value of 4.202 ng/mL. IM injections of17-HPC resulted in an average AUC_(0-t) value of 620.9 ng·hr/mL, andaverage C_(max) value of 6.144 ng/mL. C_(max) for SQ injections of17-HPC was 68.39% C_(max) for IM injections of 17-HPC. AUC_(0-t) for SQinjections of 17-HPC was 73.85% AUC_(0-t) for IM injections of 17-HPC.These results are reported in Table 1, and summarized in FIG. 1A.

TABLE 1 Summary of Results of Study Comparing HydroxyprogesteroneCaproate Plasma Concentrations After IM and SQ Injections LS LSGM #Geometric Contrast Ratio 90% Confidence P-value P-value Parameter TrtDatasets Mean (# subjects) (%) Interval (%) ISCV (%) Period SequenceAUC_(0-t) A 12 458.5 A vs B 73.85 58.87-92.63 31.4 0.0004 0.7580 nghr/mL) (SQ) (n = 12) B 12 620.9 (IM) C_(max) A 12 4.202 A vs B 68.3955.80-83.81 28.0 0.0005 0.6284 (ng/mL) (SQ) (n = 12) B 12 6.144 (IM)*Based on data in which concentrations less than the LLOQ of 0.25 ng/mLare set to 0.

FIG. 1B shows comparative results of administration of plasmaconcentration of hydroxyprogesterone caproate (ng/mL) over 168 hoursafter administration by IM (1 mL dose, 250 mg HPC) or SQ injections intoupper arm (triceps area) (1.3 mL dose, 325 mg hydroxyprogesteronecaproate.

Example 2

An open-label, randomized, single-dose, two-period, two-treatment,four-sequence, crossover study is conducted to compare: A) 17-HPC 250mg/ml given as a 1 mL deep IM injection to the upper outer quadrant ofthe gluteus maximus, B) 1 mL SQ 17-HPC 250 mg/ml injection to the upperanterior thigh, C) 17-HPC 250 mg/ml 1 mL SQ 17-HPC 250 mg/ml injectionto the upper arm (e.g., triceps area), and D) 17-HPC 250 mg/ml 1.5 mL SQ17-HPC 250 mg/ml injection to the upper anterior thigh. The study isconducted with 72 healthy, non-tobacco using postmenopausal adult women,18 per group. Blood is taken pre-dose and at 2, 4, 8, 10, 12, 18, 24,48, 72, and 120-hours post-treatment and 10, 14, 21, 28, 35 dayspost-treatment, and plasma concentrations of 17-HPC were measured. Theinterval between doses was 21 days. The analytical data are used toestimate the pharmacokinetic parameters AUC_(0-t), C_(max), and T_(max).

Example 3

A randomized study is conducted to compare the bioavailability andinjection site pain when 17-HPC, 250 mg/mL, is administered as a single1.0 mL IM injection (250 mg) in the gluteus maximus or a 1.1 (275 mg) or1.2 mL (300 mg) SQ injection in the triceps area of healthypost-menopausal women. Patients are randomized into two groups by routeof administration. Group A receives a 1.0 mL IM injection of 17-HPC intothe upper outer quadrant of the gluteus maximus. Group B receives a 1.1or 1.2 mL SC injection into the upper outer thigh or arm (triceps area).Patient reported outcomes of injection site pain are collected to assessthe safety and usability of SQ administration, either by medical staffor for self-administration of 17-HPC. (Patients in Group B can receive astandardized SQ self-administration training from nursing staff thatinvolves verbal instructions and a demonstration of proper use of SQadministration through the use of a standardized script, as well as areview of written patient instructions.) The subcutaneously administereda dose of 17-HPC by medical staff is into the upper triceps area, and/orthe anterior abdominal wall, and site personnel conduct and/or observethe procedure.

After injection, patients in groups A and B rate any pain at theinjection site with a visual analog scale (VAS), (0 mm=no pain, 100mm=worst possible pain). Patients in Group B complete an ease-of-usequestionnaire, which contains 5 statements that assess the device andthe standardized patient training for ease of use by the patient.

Secondary end points include ease-of-use questionnaire scores regardingthe device, ease-of-use and training confirmation questionnaire scoresregarding written patient instructions and SQ self-administrationtraining, assessment of essential tasks questionnaire scores,self-reported VAS scores for pain at the injection site, andinjection-site assessment numeric grades. Injection sites are assessedpredose and at 2, 4, 8, 12, 18, and 24 hours postdose. The area aroundthe injection site is evaluated for visual signs such as urticaria,swelling, and bruising, and severity is graded on a scale of 0=none,1=very slight/barely perceptible, 2=obvious, but well defined,3=moderate to severe, and 4=severe.

All patients have blood drawn prior to administration of 17-HPC, and at2, 4, 8, 12, 18 and 24 hours post dose, and again at approximately thesame time as dosing on days 2-7, 14, 21, and 28. Plasma levels of 17-HPCare measured and the analytical data are used to estimate thepharmacokinetic parameters AUC_(0-t), C_(max), and T_(max) through 42days to assess full profile from absorption through elimination. FIG. 2shows the geometric mean plasma concentrations of HPC after SC andIM—linear (left panel) and semi-logarithmic—right panel.

Adverse events and medical and surgical history are coded to systemorgan class and preferred term using the Medical Dictionary forRegulatory Activities version 14.1. An adverse event is considered to bea treatment-emergent adverse event if it starts on or afteradministration. Vital signs (including heart rate, respiratory rate, andblood pressure) are measured at screening and at 2, 4, 8, 12, 18 and 24hours post dose.

Table 2 shows results summary of pharmacokinetic parameters for HPCafter SC administration 1.1 mL (275 mg) or 1.2 mL (300 mg) in thetriceps area of the arm and IM administration of 1.0 mL (250 mg) in thegluteus maximus to healthy postmenopausal female adult subjects.

TABLE 2 SC IM Parameter* (1.1 mL) (1.2 mL) (1.0 mL) Cmax (ng/mL)  8.74(36.3) [17]  8.13 (37.5) [16]  7.08 (53.4) [14] Tmax (hr) 24.0 [17] 48.0[16] 120 [14] (18.0-168) (24.0-264) (24.0-264) AUC(0-t) (hr · ng/mL)2,773 (22.6) [17] 2,938 (24.2) [16] 2,676 (30.9) [14] AUC(inf) (hr ·ng/mL) 2,935 (22.6) [17] 3,203 (22.7) [14] 2,914 (26.5) [11] □z (1/hr)0.0031 (26.8) [17]  0.0031 (38.4) [14]  0.0031 (37.3) [11]  t½ (hr)  223 (26.8) [17]   225 (38.4) [14]   220 (37.3) [11] *Geometric mean(geometric CV[N] except Tmax for which the median [N] (range) isreported.

Table 3 shows the statistical comparison of pharmacokinetic parametersfor HPC after SC administration of 1.1 mL (275 mg) or 1.2 mL (300 mg) inthe arm and IM administration of 1.0 mL (250 mg) in the gluteus maximusto healthy postmenopausal female adult subjects.

TABLE 3 Least Squares Geometric Means Least Squares Geometric Mean Ratio(%) Power* Parameter Test Reference Estimate 90% Confidence Interval (%)SC (1.1 mL) vs. IM (1.0 mL) Cmax 8.74 7.08 123.42 96.55 □ 157.77 64.9AUC(0-t) 2,773.28 2,675.96 103.64 88.83 □ 120.91 63.7 AUC(inf) 2,934.582,913.81 100.71 86.49 □ 117.28 64.2 SC (1.2 mL) vs. IM (1.0 mL) Cmax8.13 7.08 114.81 89.51 □ 147.27 65.2 AUC(0-t) 2,937.70 2,675.96 109.7893.90 □ 128.35 63.2 AUC(inf) 3,202.63 2,913.81 109.91 93.80 □ 128.8062.7 SC (1.1 mL) vs. SC (1.2 mL) Cmax 8.74 8.13 107.50 84.82 □ 136.2464.0 AUC(0-t) 2,773.28 2,937.70 94.40 81.35 □ 109.54 65.2 AUC(inf)2,934.58 3,202.63 91.63 79.50 □ 105.61 67.5 *Power to detect at 20% at0.05.

Example 4 Formulations

Table 4 shows formulations of HPC solubilized with various ratios ofbenzyl benzoate (BB)/castor oil (CO) with and without benzyl alcohol(BA) at 5, 15, and 25° C. over 5 days. The solubility data is fairlyconstant over multiple days. Weight percent of BB is relative to thecastor oil.

Temp (° C.) Wt % BB Avg. HPC wt % mg HPC/mL solution  5° 53.01 18.60 20063.33 20.31 222 69.43 21.62 238 75.59 23.00 253 81.79 24.65 273 87.9125.22 284 15° 53.01 20.49 220 63.33 22.96 254 69.43 24.28 269 75.5925.97 289 81.79 27.32 306 87.91 28.30 320 25° 53.01 24.08 262 63.3327.17 303 69.43 28.76 321 75.59 30.62 347 81.79 31.98 363 87.91 33.26382Table 4 shows the solubility of 17-HPC with a mixture of differentratios of BB and castor oil.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

EQUIVALENTS

Various modifications of the invention an and many further embodimentsthereof, in addition to those shown and described herein, will becomeapparent to those skilled in the art from the full contents of thisdocument, including references to the scientific and patent literaturecited herein. The subject matter herein contains important information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and equivalents thereof.

1-7. (canceled)
 8. A method of reducing the risk of preterm birth in apregnant human patient, comprising: subcutaneously administering to theposterior portion of the upper arm of a pregnant human patient a 1.1 mLdose comprising a pharmaceutically acceptable non-aqueous formulationcomprising 275 mg 17-α hydroxyprogesterone caproate, wherein thesubcutaneous administration of hydroxyprogesterone caproate provides inthe patient an AUC_(0-t) of between about 120% to about 88% compared toan AUC_(0-t) of the patient administered the same dosage amount ofhydroxyprogesterone caproate intramuscularly, and wherein the dose isadministered weekly, beginning about 16 weeks or later of gestation. 9.The method of claim 8, wherein the subcutaneous administration ofhydroxyprogesterone caproate provides in the patient an AUC_(0-t) ofabout 104% compared to an AUC_(0-t) of the patient administered the samedosage amount of hydroxyprogesterone caproate intramuscularly.
 10. Themethod of claim 8, wherein the dose is subcutaneously administeredbeginning between about 16 weeks, zero days of gestation to about 20weeks, six days of gestation, and continued until about 37 weeks ofgestation or until delivery, whichever occurs first.
 11. The method ofclaim 8, wherein the pregnant human patient has a singleton pregnancy.12. The method of claim 11, wherein the pregnant human patient has ahistory of singleton spontaneous preterm birth.
 13. The method of claim8, wherein the pharmaceutically acceptable non-aqueous liquidformulation further comprises castor oil.
 14. The method of claim 13,wherein the pharmaceutically acceptable non-aqueous liquid formulationfurther comprises benzyl benzoate.
 15. The method of claim 8, whereinthe pharmaceutically acceptable non-aqueous liquid formulation consistsessentially of 17-α hydroxyprogesterone caproate, castor oil, and benzylbenzoate.
 16. A method of reducing the risk of preterm birth in apregnant human patient, comprising: subcutaneously administering to theposterior portion of the upper arm of a pregnant human patient a 1.1 mLdose comprising a pharmaceutically acceptable non-aqueous formulationcomprising 275 mg 17-α hydroxyprogesterone caproate, wherein thesubcutaneous administration of hydroxyprogesterone caproate provides inthe patient at least one of: a C_(max) of about between about 96% toabout 157% compared to a C_(max) of the patient administered the samedosage amount of hydroxyprogesterone caproate intramuscularly; anAUC_(0-t) of between about 120% to about 88% compared to an AUC_(0-t) ofthe patient administered the same dosage amount of hydroxyprogesteronecaproate intramuscularly; a C_(max) of about 8 ng/mL; and an AUC ofabout 2,770 hr·ng/mL to about 2,900 hr ng/mL, and wherein the dose isadministered weekly, beginning about 16 weeks or later of gestation. 17.The method of claim 16, wherein the subcutaneous administration ofhydroxyprogesterone caproate provides in the patient a C_(max) of aboutbetween about 96% to about 157% compared to a C_(max) of the patientadministered the same dosage amount of hydroxyprogesterone caproateintramuscularly.
 18. The method of claim 16, wherein the subcutaneousadministration of hydroxyprogesterone caproate provides in the patientan AUC_(0-t) of between about 120% to about 88% compared to an AUC_(0-t)of the patient administered the same dosage amount ofhydroxyprogesterone caproate intramuscularly.
 19. The method of claim16, wherein the subcutaneous administration of hydroxyprogesteronecaproate provides in the patient a C_(max) of about 8 ng/mL.
 20. Themethod of claim 16, wherein the subcutaneous administration ofhydroxyprogesterone caproate provides in the patient an AUC of about2,770 hr·ng/mL to about 2,900 hr ng/mL.
 21. A method of reducing therisk of preterm birth in a pregnant human patient, comprising:subcutaneously administering to the posterior portion of the upper armof a pregnant human patient a 1.1 mL dose comprising a pharmaceuticallyacceptable non-aqueous formulation comprising 275 mg 17-αhydroxyprogesterone caproate, wherein between about 24 to 48 hours afteradministration of the hydroxyprogesterone caproate dose the patient hasa mean plasma concentration of about 5 ng/mL to about 12 ng/mL, andwherein the dose is administered weekly, beginning about 16 weeks orlater of gestation.
 22. The method of claim 21, wherein between about 24to 48 hours after administration of the hydroxyprogesterone caproatedose the patient has a mean plasma concentration of between about 6ng/mL to 8 ng/mL.
 23. A method of reducing the risk of preterm birth ina pregnant human patient, comprising: subcutaneously administering tothe posterior portion of the upper arm of a pregnant human patient a 1.1mL dose comprising a pharmaceutically acceptable non-aqueous formulationcomprising 275 mg 17-α hydroxyprogesterone caproate, wherein thesubcutaneous administration of hydroxyprogesterone caproate provides inthe patient a T_(max) of between about 18 hours to about 168 hours. 24.The method of claim 23, wherein the subcutaneous administration ofhydroxyprogesterone caproate provides in the patient a T_(max) of about24 hours.
 25. The method of claim 8, wherein the dosage is administeredby a healthcare professional.
 26. The method of claim 16, wherein thedosage is administered by a healthcare professional.
 27. The method ofclaim 21, wherein the dosage is administered by a healthcareprofessional.
 28. The method of claim 23, wherein the dosage isadministered by a healthcare professional.